What is the first‑line drug and dosing for leptospirosis in a healthy adult, and what alternatives are used for pregnancy, penicillin allergy, severe disease, and children?

Drug Treatment for Leptospirosis

For mild‑to‑moderate leptospirosis in healthy adults, oral doxycycline 100 mg twice daily for 7 days is first‑line therapy; for severe disease requiring hospitalization, intravenous penicillin G 1.5 million units every 6 hours or ceftriaxone 1 g daily for 7 days are equally effective. 1, 2, 3

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First‑Line Treatment by Disease Severity

Mild‑to‑Moderate Leptospirosis (Outpatient)

• Doxycycline 100 mg orally twice daily for 7 days is the preferred oral agent for ambulatory patients with mild disease 2, 3
• Azithromycin appears promising for less severe disease, though evidence is limited compared to doxycycline 2
• Oral penicillin has been traditionally used but lacks robust evidence demonstrating superiority over placebo for mortality, fever duration, or hospital stay 4, 3

Severe Leptospirosis (Hospitalized Patients)

• Intravenous penicillin G 1.5 million units every 6 hours for 7 days has been the traditional treatment of choice for severe disease 1, 2, 3
• Ceftriaxone 1 g intravenously once daily for 7 days is equally effective as penicillin G, with the advantage of once‑daily dosing and broader antimicrobial spectrum 1, 2
• Cefotaxime is also an acceptable alternative third‑generation cephalosporin for severe leptospirosis 2

The median time to fever resolution is 3 days with either penicillin G or ceftriaxone, with no significant differences in duration of organ dysfunction or mortality (approximately 5% in both groups). 1

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Special Populations and Alternative Regimens

Pregnancy

• Penicillin G remains the safest option during pregnancy, as doxycycline is contraindicated (pregnancy category D) 2
• Ceftriaxone 1 g IV daily is a reasonable alternative if penicillin allergy exists, though specific pregnancy data are limited 1, 2

Penicillin Allergy

• Doxycycline 100 mg orally twice daily for mild disease or intravenously for severe disease is the primary alternative 2, 3
• Ceftriaxone or cefotaxime can be used if the penicillin allergy is not an immediate hypersensitivity reaction (cross‑reactivity with cephalosporins is low but possible) 1, 2
• Fluoroquinolones (e.g., levofloxacin, moxifloxacin) show promise but lack adequate human trial data to fully support their use 2

Pediatric Patients

• For children ≥8 years: doxycycline 2 mg/kg twice daily (maximum 100 mg per dose) for 7 days 2
• For children <8 years: avoid doxycycline due to risk of permanent tooth discoloration and impaired bone growth; use penicillin G 100,000–150,000 units/kg/day divided every 4–6 hours for severe disease 2
• Amoxicillin 40 mg/kg/day divided every 8 hours may be considered for mild disease in children, though evidence is limited 2

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Chemoprophylaxis

High‑Risk Exposure Settings

• Doxycycline 200 mg orally as a single dose at the time of exposure to flood water may reduce symptomatic infection (OR 0.23; 95% CI 0.07–0.77) 4, 5
• Weekly doxycycline 200 mg for soldiers training in endemic areas with high exposure risk reduces symptomatic leptospirosis from 4.9% to 0.6% (number needed‑to‑treat 24) 5
• Prophylaxis is not routinely recommended for general populations in endemic areas, as the evidence applies primarily to military personnel with intense short‑term exposure 5

Adverse Effects of Prophylaxis

• Doxycycline prophylaxis causes adverse effects in 3% of recipients versus 0.2% with placebo (number needed‑to‑harm 39), including gastrointestinal upset and photosensitivity 5

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Evidence Quality and Treatment Limitations

Critical Evidence Gaps

• No antibiotic regimen has demonstrated statistically significant reduction in mortality compared to placebo in meta‑analysis (OR 1.65; 95% CI 0.76–3.57 for penicillin) 4, 3
• Penicillin does not reduce time to defervescence (mean difference −0.16 days; 95% CI −1.4 to 1.08), hospital stay, incidence of oliguria/anuria, need for dialysis, or liver function normalization time compared to placebo 4, 3
• Despite these limitations, antibiotics (particularly penicillin and doxycycline) reduce leptospiruria (5% vs. 40% with placebo; risk difference −46%) and may shorten prolonged hospital stays (>7 days: 30% vs. 74% with placebo) 3

Comparative Efficacy

• No significant differences exist between penicillin, cephalosporins (ceftriaxone/cefotaxime), and doxycycline in head‑to‑head trials for severe leptospirosis 1, 4
• The choice among these agents should be guided by route of administration preference, allergy history, pregnancy status, and local availability 1, 2

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Practical Treatment Algorithm

Step 1: Assess Disease Severity

• Mild disease (outpatient): fever, myalgia, headache without organ dysfunction → oral doxycycline 100 mg twice daily × 7 days 2, 3
• Severe disease (hospitalized): jaundice, renal failure, pulmonary hemorrhage, hemodynamic instability → IV penicillin G 1.5 million units every 6 hours or ceftriaxone 1 g daily × 7 days 1, 2

Step 2: Identify Contraindications

• Pregnancy: use penicillin G or ceftriaxone; avoid doxycycline 2
• Children <8 years: use penicillin G; avoid doxycycline 2
• Penicillin allergy: use doxycycline or ceftriaxone (if non‑immediate hypersensitivity) 1, 2

Step 3: Consider Prophylaxis Only in High‑Risk Scenarios

• Single‑dose doxycycline 200 mg at time of flood water exposure in endemic areas 4, 5
• Weekly doxycycline 200 mg for military personnel or occupational groups with intense short‑term exposure 5

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Common Pitfalls and Caveats

• Do not withhold antibiotics despite limited mortality benefit; they reduce leptospiruria and may shorten severe illness duration 4, 3
• Do not use doxycycline in pregnancy or children <8 years; penicillin G is the safest alternative 2
• Do not assume fluoroquinolones are equivalent to doxycycline or penicillin; human trial data are insufficient 2
• Do not routinely prescribe prophylaxis to general populations in endemic areas; evidence supports use only in high‑risk occupational or military settings 5
• Ceftriaxone may be preferred over penicillin G in severe disease due to once‑daily dosing, broader spectrum (covering co‑infections), and equal efficacy 1, 2

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Urgent Need for Better Evidence

Well‑designed clinical trials including quinolones, aminoglycosides, and other antibiotics are urgently needed, as current evidence shows no clear mortality benefit for any regimen, and leptospirosis remains a neglected disease with suboptimal treatment guidance 4